Hydrazides of pyridazonyl-substituted alkanoic acids



Unite rates HYDRAZIDES )F PYAZONYL-SUBSTITUTED ALKANOEQ ACIDS John A.King, Manhasset, N. Y., assignor to Warner- Larnhert Pharmaceutieal(Iompany, New York, N. Y., a corporation of Delaware No Drawing.Application September 14, 1955 Serial No. 534,385

8 Claims. (Cl. 260-250) This invention relates to a new class ofcompounds which are or" value as pharmaceuticals, especially as woundhealing agents.

The new compounds of my invention are represented by the followinggeneric formula:

wherein and Z denotes a direct linkage, an unsubstituted alkylene chaincontaining not more than 20 carbon atoms, or a lower alkyl-substitutedalkylene chain containing not more than 20 carbon atoms.

The new compounds of my invention may be prepared in accordance with thefollowing general scheme:

wherein R R R R, R and Z are as indicated above, R is lower alkyl and Xis halogen.

The pyridazone derivatives used as starting materials in the schemeindicated above are prepared by various methods depending upon thenature of the substituents in the pyridazone nucleus. below; and in thereaction schemes shown the methyl radical is used as an illustration ofthe lower alkyl radical; however the said methyl radical may be replacedby hydrogen or by other lower alkyl radicals without prejudicing theoperability of the said reaction schemes.

The said pyridazone derivatives of the formula are prepareby thefollowing methods:

These methods are discussed atent O ice COOCa s CHs-CH-O O OH H; +NHgNHzoooon on, on, on,

0 Hole Heat A NE NH NH nooo \N/ 11000 \N/ \N/ This compound may bealt'erna'tii'rely prepared by method D.

Method D'.

Method E.-R ="R "=CH R =H. This pyridaione may be obtained as follows:

GET-000E.

OH -0H Method F. R =R =CH R =H [see Gazz. chim,

ital. 70, 768 (1940)]. This pyridazone is prepared as follows:

CHr-CH-C O OH Method G.R =H, R =R =CH This pyridazone is prepared asfollows:

CHICHCOOC2H5 CH:- H

+ EzNNHa Method H.-R =R =R =CH prepared as follows:

CHa-CH-COOH OH:- H

OHPOO This pyridazone is zNNHa CH; OH:

on o CH HOAe 1 NH NH CH \N/ CH \N/ PREPARATION OF PYRTDAZONES Example1.-methyl-6-pyridazone A solution of3-carboxy-5-methyl-4,5-dihydro-6-pyridazone (32g, 0.205 mole) [Bill].Soc. Chim. (4) 9, 451 (1911)] in 200 ml. of glacial acetic acid washeated to boiling and, with stirring, bromine (33.6 g., 0.21 mole) wasadded dropwise. After the addition was complete the mixture was heatedat reflux for fifteen minutes and then diluted with 200 ml. of water andevaporated to dryness under vacuum. The residue was crystallized from1500 ml. of water giving 28.0 g. of crystals melting at 275 C. (dec.);the thus obtained 3-carboxy-5-methyl-6- pyridazone (27 g., 0.175 mole)was heated at atmospheric pressure until the material was all meltedafter which it was distilled at 100 mm. pressure giving 16 g. ofdistillate; this distillate was crystallized from 350 ml. of benzenegiving g. (52% yield) of the desired material melting at l58-l59 C.

Example 2.-3,4- dimethyl-6-pyridazone 4 tion was evaporated to drynessunder vacuum leaving 12.6 g. of crystalline3,4-dimethyl-4,5-dihydro-6-pyridazone which melted at 98-l08 C. Aportion after two recrystallizations from Skellysolve C melted at 111.5-112.5 C. By the bromine dehydrogenation procedure described in Example 13,4-dimethyl-4,5-dihydro-5-pyridazone gave after crystallization fromwater an 81% yield of the desired 3,4-dimethyl-6-pyridazone melting at225-228 C. A small sample after recrystallization from benzene melted at232233 C.

Example 3.-3,5-dimethyl-6-pyridaz0ne As described in Example 2 for the3,4-dimethyl isomer, a-methyllevulinic acid and hydrazine in ethanolgave 3,5- dimethyl-4,5-dihydro-6-pyridazone melting at 59.5-62.5 C. Asmall portion after recrystallization from Skellysolve C melted at62.5-63.5 C. A solution of 3,5-dimethyl-4,5-dihydro-6-pyridazone (10.0g., 0.079 mole) in ml. of glacial acetic acid was heated to boiling andbromine (12.9 g., 0.079 mole) was added dropwise to the stirred solutionafter which the mixture was heated at reflux for fifteen minutes. Thereaction mixture was diluted with 75 ml. of water and evaporated todryness under vacuum. The residue was crystallized from 10 ml. of watergiving 3.0 g. of material which melted at 240 C. (dec.); this materialwhich after recrystallization from a little methanol, melted at 255 C.(dec.) gave a strong ionic halogen test and was the hydrobromide of3,5-dimethyl-6-pyridazone. The original water mother liquor wasneutralized with sodium hydroxide solution and the neutral solution wasevaporated to dryness under vacuum. The residue was boiled with 30 ml.of benzene and the resulting suspension was filtered. The chilledbenzene filtrate gave 6.0 g. (61% yield) of 3,5-dimethyl-6-pyridazonemelting at 126-128 C. A small sample after recrystallization fromSkellysolve C melted at l30-131 C.

Example 4.3,4,5-trimetlzyl-6-pyridaz0ne or,]3-Dimethyllevulinic acid(14.4 g., 0.10 mole) [Ber., 44, 2191 (1911)] and hydrazine hydrate (5.0g., 0.10 mole) were mixed in ethanol and the solution was evaporated todryness under vacuum. The viscous residue was distilled giving acrystalline distillate of 3,4,5-trimethyl- 4,5-dihydro-6-pyridazoneboiling at 79 C./ 0.1 mm. which was recrystallized from Skellysolve Bgiving 8.5 g. of material melting at -86 C. A solution of3,4,5-trimethyl- 4,5-dihydro-6-pyridazone (57 g., 0.41 mole) in 250 ml.of glacial acetic acid was heated to boiling, and with stirring, bromine(65.5 g., 0.41 mole) was added dropwise to the solution. After theaddition was complete the solution was heated at reflux for fifteenminutes after which the acetic acid was distilled off under vacuum. Theresidue was dissolved in 200 ml. of water and this solution was broughtto pH 7 with sodium hydroxide solution. An orange-yellow solidprecipitated which weighed 42 g. (74% yield) was melted at 238-245 C. Asmall sample after recrystallization from ethyl acetate and again fromwater melted at 249.5-250" C.

Example 5 .-3-ethyl-6-pyridazone A solution of3-ethyl-4,5-dihydro-6-pyridazone (40.5 g., 0.322 mole) [Ber., 81, 1(1948)] in 160 ml. of glacial acetic acid was heated to boiling and thesolution was treated dropwise with bromine (52 g., 0.325 mole). Afterthe addition wascomplete the mixture was heated under refiux for fifteenminutes. The reaction mixture was then diluted with ml. of water andevaporated to dryness under vacuum. The residue was dissolved in 200 ml.of water and this solution was neutralized with sodium hydroxidesolution after which the solution was evaporated to dryness undervacuum. The residue was boiled with 250 ml. of absolute ethanol and thesodium bromide removed by filtration. The alcohol was evaporated fromthe filtrate and the residue was distilled giving 17 g. (42.5%) ofmaterial which slowly crystallized. A small sample afterrecrystallization from Skellysolve B melted at 95 C.

PREPARATION OF PYRiDAZONYL-SUBSTITUTED ALKANOIC ESTERS Example 6.Ethyl8-(3-methyl-6-pyridaz0nyl-1) propi-onate To a solution of sodium (12.7g., 0.55 mole) in 450 ml. of absolute ethanol there was added3-methyl-6- pyridazone (60.5 g., 0.55 mole). This solution was stirredat less than 20 C. while ethyl ,B-bromopropionate (100 g., 0.55 mole)was added dropwise. When the addition was complete the reaction mixturewas heated under refiux for three hours after which it was cooled andfiltered to remove sodium bromide. The ethanol was removed from thefiltrate by distillation under vacuum andv the residue was taken up in250 ml. of benzene. The benzene solution was washed with three 100 ml.portions of water to remove residual sodium bromide and unreactedpyridazone after which the benzene was stripped oil under vaccum and theresidue was distilled giving 53.5 g. (46.5% yield) of material boilingat 124 C. (0.5 mm).

Example 7.-Ethyl w-(3-methyl-6-pyrizlazonyl-1)zmdecanoate When ethylw-bromoundecanoate [1. Chem. Soc. 79, 1191 (1901)] was used to alkylate3-methyl-6-pyridazone in a manner similar to that described in Example6, there was obtained ethyl w-(3-methyl-6-pyridazonyl-1)undecanoate in47.5% yield boiling at 166170 C; (.04 mm.).

Example 8.Ethyl a-(3-methyl-6-pyridaz0nyl-1)-nbutyrate By the sameprocedure as in Example 6, ethyl a-bromon-butyrate and3-methyl-6-pyridazone gave ethyl a-(3-methyl-6-pyridazonyl-1)-n-butyrate in 79% yield boiling at 92 C. (.05mm.).

Example 9.-Ethyl u-(3-methyl-6-pyridazonyl-l )-n-valerate This ester wasobtained from ethyl m-bromo-n-valerate in 82.5% yield boiling at 111(0.15 mm.).

Example l0.--Ethyl oc-(3-methyl-6-pyridazonyl-l )-caproate This esterwas obtained from ethyl a-bromo-n-hexanoate in 79.5% yield boiling at117 (0.3 mm).

Example 11.Ethyl a-(3-methyl-6-pyridazonyl-I )-n-heptan0ate This esterwas prepared from ethyl a-hromo-n-heptanoate in 63% yield boiling at 129(0.2 mm).

Example 12.Ethyl-a-phenyl-a-(3methyl-6- pyriaazonyl-l) acetate To asolution of sodium (15.5 g., 0.675 mole) in 700 ml. of absolute ethanolthere was added with stirring S-methyl-G-pyridazone (74.5 g., 0.675mole). The reaction mixture was cooled to less than 10 C. while ethyla-bromophenylacetate (164 g., 0.675 mole) was added dropwise. When theaddition was complete, the reaction mixture was heated at 50 C. for onehour. The sodium bromide was filtered off while the reaction mixture wasstill hot. The filtrate was concentrated to 500 ml. under vacuum, heatedto the boiling point and filtered. The chilled filtrate yielded crystals(69.5 g., 38%) which melted at 119-122 C. A small sample, recrystallizedfrom absolute ethanol, melted at 121- 123 C.

of absolute ethanol there was added 5-methyl-6-pyridazone (33 g., 0.3mole). This solution was stirred at less than 10 C. while ethyla-bromoacetate (50 g., 0.3 mole) was added dropwise. After the additionwas complete, the reaction mixture was heated under reflux for one hourafter which it was cooled and filtered to remove sodium bromide. Thefiltrate was evaporated to dryness under vacuum and the residue wasdissolved in 250 ml. of benzene. The benzene solution was washed withtwo ml. portions of water and was dried over anhydrous sodium sulfate.The benezene was evaporated under vacuum and the residue wascrystallized from 300 ml. of Skellysolve C. The product weighed 24 g.(41% yield) and melted at 7576 C.

Example 14.Ethyl (3,5-dimethyl-6-pyridazonyl-I) acetate By a proceduresimilar to that of Example 13, 3,5-dimcthyl-o-pyridazone and ethylbromoacetate gave this ester in 40% yield melting at 107-108 C.

Example 15.--Etlzyl (3,4-dimethyl-6-pyridazOnyl-l )acetate By theprocedure used to prepare ethyl ,8-(3-methyl- 6-pyridazonyl-1)propionate (Example 6), 3,4-dimethyl- 6-pyridazone and ethylbromoacetate gave ethyl (3,4-dimethyl-6-pyridazonyl-1) acetate in 69%yield boiling at 130 C. (0.2 mm.).

Example 16.Ethyl (3,4,5-trimethyl-6-pyridazone-1 )acetate To a solutionof sodium (4.6 g., 0.2 mole) in 200 ml. of absolute ethanol there wasadded 3,4,5-trimethyl-6- pyridazone (27.6 g., 0.2 mole). This solutionwas stirred at less than 10 C. while ethyl bromoacetate (33.4 g., 0.2mole) was added dropwise. After the addition was complete the reactionmixture was heated under reflux for one hour. An additional 100 ml. ofabsolute ethanol was added and the boiling mixture was filtered to re.-move sodium bromide. The filtrate was chilled giving 24 g. (54% yield)of material melting at 122-426 C.

Example 17.-Ethyl (.3-ethyl-6-pyridazonyl-1 )acetate By the procedureused to prepare ethyl B-(3-methyl-6- pyridazonyl-l) propionate (Example6), 3-ethyl -6-pyridazone and ethyl bromoacetate gave ethyl(3-ethyl-6-pyridazonyl-1)acetate in 70% yield boiling at -111" C. (0.09mm.). This material later crystallized and melted at 48-50 C.

Example 18.--Ethyl (S-phenyl-6-pyridaz0nyl 1)acetate By the procedureused to prepare ethyl (3,4,5-trimethyl- 6-pyridazonyl-l)-acetate(Example 16), 3-phenyl-6-pyridazone [Ber., 32, 395 (1899)] and ethylbromoacetate gave ethyl (3-phenyl-6-pyridazonyl-1)acetate in 66% yieldmelting at 100-102 C.

Example 19.Ethyl B-(p-bromophenyl) -6- pyridazdnyl-I -acetate By theprocedure used to prepare ethyl (3,4,5-trimethyl- 6 pyridazonyl 1)acetate (Example 16), 3 (p bromophenyl)-6-pyridazone [1. A. C. S. 75,1117 (1953)], and ethyl bromoacetate gave ethyl3-(p-bromophenyl)-6-pyridazonyl-l-acetate in 53% yield melting at171-172" C.

PREPARATION OF HYDRAZiDES All of the hydrazides of my invention wereprepared by heating the corresponding ester with'a slight excess ofhydrazine hydrate in a solvent, usually ethanol, after which the solventwas removed under vacuum and the residue was crystallized from asuitable solvent. Certain of the esters with higher molecular weights orwith a greater amount of steric hindrance required higher temperaturesfor the reaction to proceed. These reactions were carried out inn-propanol. Examples of the hydrazides of my invention with pertinentdata concerning preparation and properties, are listed in Table I.

Table l.-Hydrazides Example Reaction Reaction M. P., Percent N 0. Nameof Hydrazide Tgrgp Reerystn. Solvent 0. Yield fi-Pyridazonyl-l-acetic 803 Aqueous ethano1 213-216 72 3-Methyl-fi pyridazonyl-l-acetic 80 1 d199-200 88 B-(3-Methyl-6-pyridazonyl-1)propiomc" 80 2 Ethanol 151-153 80w-(3-Methyl-6-pyridazonyl-1) undecanoic. 120 24 Benzene Skellysolve B.85-87 18 a-(3-Methyl-6-pyridazonyl-l) propionim. 80 1 Ethanol 134.5-13565 a-(3-Methyl-6-pyridazonyl-l) butyr1c 80 6 Benzene" 125. 5-127 77a-(B-Methyl-G-pyridazonyl-l) 171118110. 80 1 d 112-115 44a-(B-Methyl-G-pyridazonyl-l) heptanoie 80 21 Benzene Skellysolve B108-109 53 a-Phenyl-a-(Ii-methyl-G-pyridazonyl-l) acetic 130 24 Ethanol191-192 79 zx-(ll-Methyl-6-pyridazonyl-l) isobutyric 120 65 o e. 165-16622 -Methyl-6-pyridazonyl-l-acetic 80 12 Aqueous EthanoL. 203-21115 733,5-Dimethyl-G-pyrldazonyl-l-acetic 80 2 Ethanol 19 1-196 443,4-Dimethyl-6-pyridazonyl-1-eeetie 80 5 Aqueous Ethanol- 205-206 783,4,5-Trlmethyl-6-pyridazonyl-l-acutie 80 1'2 7 d0 .1 217-221 793-Ethyl-6-pyridazonyl-1-acetio. S0 4 Ethanol. 170-171 653-Phenyl-S-pyrldazonyl-l-acetic S0 2 Water. 211-213 753-(pFBromophenyl)-6-pyridazonyl-1-a 100 4 Ethanol 223-226 56 I claim: 20which comprises reacting hydrazine with a composition of 1. A compoundhaving the structural formula the following structural formulaN-Z--OONHNH: 1

N wherein wherein R denotes lower alkyl and R R R R R and R denotes amember selected from the group consisting Z are as defined m clam fhydrogen and lower alkyl 8. The process of preparing the compounds ofclalm 1, R denotes a member selected from the group consisting WhlchcomPl'lse reacting a Pyndazone of the following of hydrogen, lower alkyland phenyl Structural formula R denotes a member selected from the groupconsisting m of hydrogen, halogen, lower alkyl, phenyl and halophenyl R0 R denotes a member selected from the group consisting of hydrogen andlower alkyl Ra 9 R denotes a member selected from the group consisting Nof hydrogen and lower alkyl; and 40 with an ester of the followingformula Z denotes a member selected from the group consisting of adirect linkage and an alkylene chain of not more than 20 carbon atoms XZC COOR 2. w-(3-methyl-6-pyridazonyl-1)undecanoic hydrazide. 3. a(3-methyl- 6-pyridazonyl- 6 -pyridazonyl-1)- in the presence of analkali metal alkoxide, and therepropionhydrazide. after reacting theresulting product with hydrazine, 4.a-Phenyl-a-(3-methyl-6-pyridazonyl-1)acethydrazide. wherein R denoteslower alkyl, X denotes halogen, and 5.3,4,5-trimethyl-6-pyridazonyl-l-acethydrazide. R R R R R and Z are asdefined in claim 1. 6. 3-(p-bromophenyl)-6-pyridazonyl-l-acethydrazide.m

7. The process of preparing the compounds of claim 1 N 0 referencescited.

1. A COMPOUND HAVING THE STRUCTURAL FORMULA